Attenuation of neomycin ototoxicity by iron chelation.
Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential (CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.
Conlon
B J
BJ
Division of Otolaryngology-Head and Neck Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Perry
B P
BP
Smith
D W
DW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001309:Auditory Threshold / Q000187:drug effects; D003676:Deferoxamine / Q000627:therapeutic use*; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005609:Free Radicals; D006168:Guinea Pigs; D006311:Hearing Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D009355:Neomycin / Q000009:adverse effects*
D000900:Anti-Bacterial Agents; D005609:Free Radicals; D007502:Iron Chelating Agents; D009355:Neomycin; D003676:Deferoxamine